Elsevier

Chemico-Biological Interactions

In vitro alkylation of calf thymus Dna by acrylonitrile. Isolation of cyanoethyl-adducts of guanine and thymine and carboxyethyl-adducts of adenine and cytosine

Abstract

Reaction of the rodent carcinogen acrylonitrile (AN) at pH 5.0 and/or pH 7.0 for 10 and/or forty days with 2′-deoxyadenosine (dAdo), 2′-deoxycytidine (dCyd), 2′-deoxyguanosine (dGuo), 2′-deoxyinosine (dIno), Nsix-methyl-2′-deoxyadenosine (Nsix-Me-dAdo) and thymidine (dThd) resulted in the formation of cyanoethyl and carboxyethyl adducts. Adducts were not detected after 4 h. The adducts isolated were 1-(2-carboxyethyl)-dAdo (one-CE-dAdo), Nhalf dozen-CE-dAdo, 3-CE-dCyd, seven-(2-cyanoethyl)-Gua (vii-CNE-Gua), vii,9-bis-CNE-Gua, imidazole ring-opened 7,9-bis-CNE-Gua, 1-CNE-dIno, 1-CE-Nhalf dozen-Me-dAdo and 3-CNE-dThd. Structures were assigned on the basic of UV spectra and electron affect (EI), chemical ionization (CI), desorption chemical ionization (DCI) and Californium-252 fission fragment ionization mass spectra. Evidence is presented which strongly suggests that N6-CE-dAdo was formed by Dimroth rearrangement of 1-CE-dAdo during the reaction between AN and dAdo. The carboxyethyl adducts resulted from initial cyanoethylation (by Michael addition) at a ring nitrogen adjacent to an exocyclic nitrogen atom followed by rapid hydrolysis of the nitrile moiety to a carboxylic acrid. It was postulated that the facile hydrolysis is an autocatalyzed reaction resulting from the germination of a cyclic intermediate between nitrile carbon and exocyclic nitrogen. AN was reacted with calf thymus DNA (pH 7.0, 37°C, twoscore days) and the relative amounts of adducts isolated were ane-CE-Ade (26%), Due north6-CE-Ade (8%), 3-CE-Cyt (ane%), vii-CNE-Gua (26%), 7,9-bis-CNE-Gua (4%), imidazole band-opened vii,9-bis-CNE-Gua (19%) and 3-CNE-Thy (16%). Thus a carcinogen once adducted to a base in Deoxyribonucleic acid was shown to be subsequently modified resulting in a mixed pattern of cyanoethylated and carboxyethylated AN-Deoxyribonucleic acid adducts. Iii of the adducts (1-CE-Ade, N6-CE-Ade and 3-CE-Cyt) were identical to adducts previously reported by us to exist formed following in vitro reaction of the carcinogen β-propiolactone (BPL) and calf thymus Deoxyribonucleic acid. The results demonstrate that AN can straight alkylate Dna in vitro at a physiological pH and temperature.

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